| Pharmaceutically active 4,6-disubstituted aminopyrimidine derivatives as modulators of protein kinases -> Monitor Keywords |
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Pharmaceutically active 4,6-disubstituted aminopyrimidine derivatives as modulators of protein kinasesRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai, Hetero Ring Is Seven-membered Consisting Of One Nitrogen And Six Carbons, Additional Hetero Ring Attached Directly Or Indirectly To The Seven-membered Hetero Ring By Nonionic Bonding, The Additional Hetero Ring Is Six-membered And Contains Nitrogen, Plural Ring Hetero Atoms In The Additional Hetero Ring,Pharmaceutically active 4,6-disubstituted aminopyrimidine derivatives as modulators of protein kinases description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070191344, Pharmaceutically active 4,6-disubstituted aminopyrimidine derivatives as modulators of protein kinases. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] The present invention relates to 4,6-disubstituted aminopyrimidine derivatives and/or pharmaceutically acceptable salts thereof, the use of these derivatives as pharmaceutically active agents, especially for the prophylaxis and/or treatment of infectious diseases, including opportunistic diseases, prion diseases, immunological diseases, autoimmune diseases, bipolar and clinical disorders, cardiovascular diseases, cell proliferative diseases, diabetes, inflammation, transplant rejections, erectile dysfunction, neurodegenerative diseases and stroke. Furthermore, the present invention is directed towards pharmaceutical composition containing at least one of the 4,6-disubstituted aminopyrimidine derivatives and/or pharmaceutically acceptable salts thereof. [0002] One of the most important and fundamental processes in biology is the division of cells during the cell cycle. This process ensures the controlled production of subsequent generations of cells with defined biological function. It is a highly regulated phenomenon and responds to a diverse set of cellular signals both within the cell and from external sources. Cyclin dependent kinases (CDKs) play a key role in regulating the cell cycle machinery. These complexes consist of two components: a catalytic subunit (the kinase) and a regulatory subunit (the cyclin). To date, eleven kinase subunits have been identified (S. Mani et al., Exp. Opin. Invest. Drugs 2000, 9(8), 1849-1870, J. C. Sergere et al., Biochem. Biophys. Res. Commun. 2000, 276, 271-277, D. Hu et al, J. Biochem. Chem. 2003, 278(10), 8623-8629). [0003] It is known, that CDKs play a role in the regulation of cellular proliferation. Therefore, CDK inhibitors could be useful in the treatment of cell proliferative disorders such as cancer, neuro-fibromatosis, psoriasis, fungal infections, endotoxic shock, transplantation rejection, vascular smooth cell proliferation associated with arteriosclerosis, pulmonary fibrosis, arthritis, glomerulonephritis and post-surgical stenosis and restenosis (U.S. Pat. No. 6,114,365). [0004] CDKs are also known to play a role in apoptosis. Therefore CDK inhibitors could be useful in the treatment of cancer; autoimmune diseases, for example systemic lupus, erythematosus, autoimmune mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, and autoimmune diabetes; neurodegenerative diseases for example Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotrophic lateral scelrosis, retinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration; myelodysplastic syndromes, aplastic anemia, ischemic injury associated with myocardial infarctions, stroke and reperfusion injury, arrhythmia, atherosclerosis, toxin-induced or alcohol related liver diseases; hematological diseases, for example, chronic anemia and aplastic anemia; degenerative diseases of the musculoskeletal system, for example, osteoporosis and arthritis, cystic fibrosis, multiple sclerosis, kidney diseases and cancer pain and for the treatment of cardiovascular diseases (U.S. Pat. No. 6,107,305 and WO 02/100401). Further it is known, that CDK inhibitors could be used for the treatment of virally induced infectious diseases, such as EBV, HBV, HCV and HIV (WO 02/100401). [0005] Recently, it was described, that HIV-1 replication could be affected by inhibiting CDKs (C. de la Fuenta, Current HIV research, 2003, 1(2), 131-152; Y. K. Kim et al., Molecular and Cellular Biology, 2002, 22(13), 4622-4637). Especially CDK9 is reported to be essential for the HIV-1 replication (H. S. Mancebo et al, Genes Dev. 1997, 11(20): 2633-44, O. Flores et al., Proc Natl. Acad. Scd. U S A. 1999, 96(13):7208-13). [0006] Most of the known CDK inhibitors, such as olomoucine, roscovitine, CYC202, purvalanols, indolinones, paullones and 7-hydroxy-staurosporine are focusing on the inhibition of CDK1 and CDK2 with the goal of antitumor activity (Current opinion in Pharmacology, 2003, 3, 1-9). A summary of the known CDK-inhibitors is given by M. Huwe et al. (A. Huwe et al., Angew Chem Int Ed Engl. 2003; 42(19): 2122-38). [0007] Flavopiridol is described as a low-molecular, but unselective inhibitor of CDKs, including CDK9 (W. Filgueira de Azevedo et al., Biochem. and Biophys. Res. Commun. 2002, 293(1), 566-571). Other compounds that were shown to inhibit CDKs are staurosporine, fascaplysin and hymenialdisine. [0008] The use of 4-Aminopyrimidine derivatives as neuroprotective agents is described in WO 02/12198. These compounds generally contain as a basic residue a substituted amine in para position of the anilino part of the molecule and it is stated, that these compounds did not inhibit MEK1/2 kinase activity in P19 neurons. [0009] U.S. Pat. No. 3,950,25 describes the use of 4-Amino-6-aryl-pyrimidines as platelet aggregation inhibitors and bronchodilators. U.S. Pat. No. 3,478,030 describes the synthesis of benzamide substituted anilino aminopyrimidine derivatives. These compounds are used as potent dilators of coronary arteries. WO 02/79197 describes the use of aryl-substituted 2-aminopyrimidine derivatives as protein kinase inhibitors, for example as inhibitor of JNK, GSK-3, Src, Lck or CDK2. [0010] There is a high unmet medical need to develop CDK inhibitors, useful in treating various conditions associated with CDK activation, in particular concerning CDK9 kinase activity, which is associated with HIV replication. [0011] It is object of the present invention to provide compounds and/or pharmaceutically acceptable salts thereof which can be used as pharmaceutically active agents, especially for prophylaxis and/or treatment of infectious diseases, including opportunistic diseases, prion diseases, immunological diseases, autoimmune diseases, bipolar and clinical disorders, cardiovascular diseases, cell proliferative diseases, diabetes, inflammation, transplant rejections, erectile dysfunction, neurodegenerative diseases and stroke, methods to treat said diseases, as well as compositions comprising at least one of those compounds and/or pharmaceutically acceptable salts thereof as pharmaceutically active ingredients. Another object of the present invention is to provide a medium and a method, which are capable of specifically enriching nucleotide-binding proteins such as protein kinases from a pool of proteins, such as a proteome, a cell lysate or a tissue lysate. [0012] This object is solved by the compounds and/or their pharmaceutically acceptable salt according to independent claim 1, the compounds of the present invention for use as a pharmaceutically active agents according to independent claim 34, the use of the compounds of the present invention for the preparation of a pharmaceutical composition for the prophylaxis and/or treatment of infectious diseases, including opportunistic diseases, prion diseases, immunological diseases, autoimmune diseases, bipolar and clinical disorders, cardiovascular diseases, cell proliferative diseases, diabetes, inflammation, transplant rejections, erectile dysfunction, neurodegenerative diseases and stroke, the use of compounds according to the present invention as inhibitors for a protein kinase according to independent claim 54, the pharmaceutical compositions according to claim 57, the medium according to claim 58, and the method for enriching, purifying or depleting nucleotide binding proteins according to independent claim 66. [0013] Further advantageous features, aspects and details of the invention are evident from the dependent claims, the description, the examples and the drawings. The novel 4,6-disubstituted aminopyrimidine compounds according to the present invention are defined by the general formula (I) wherein [0014] R.sup.1 is selected from the group comprising: [0015] --H, linear or branched C.sub.1-C.sub.6 substituted or unsubstituted alkyl, linear or branched C.sub.2-C.sub.6 alkenyl or linear or branched C.sub.2-C.sub.6 alkinyl; [0016] R.sup.2 and R.sup.4 are independently selected from the group consisting of: [0017] --H, linear or branched C.sub.1-C.sub.6 substituted or unsubstituted alkyl, linear or branched C.sub.2-C.sub.6 alkenyl, linear or branched C.sub.2-C.sub.6 alkinyl, aryl, --F, --Cl, --Br, --I, --CN, --NH.sub.2 or --NO.sub.2; [0018] R.sup.3 is selected from the group comprising: [0019] --F, --Cl, --Br, --I, substituted or unsubstituted aryl, substituted or unsubstituted --O-aryl, --NH-aryl, --S-aryl, or substituted or unsubstituted --O-heterocyclyl, --NH-heterocyclyl, --S-heterocyclyl, or substituted or unsubstituted --CH.dbd.CH-aryl, or substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclyl, or substituted or unsubstituted C.sub.3-C.sub.8 cycloalkyl, or --NH--(CH.sub.2).sub.n--X, wherein n is an integer from 0 to 6 and X is selected from --OH, --NH.sub.2 or substituted or unsubstituted C.sub.3-C.sub.8 cycloalkyl; [0020] R.sup.5 is selected from the group consisting of: [0021] Substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted C.sub.3-C.sub.8 cycloalkyl, or --(CH.sub.2).sub.o--Y, wherein o is an integer from 0 to 6 and Y represents substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl or substituted or unsubstituted C.sub.3-C8 cycloalkyl; [0022] R.sup.6 is selected from the group consisting of: [0023] --H, linear or branched substituted or unsubstituted C.sub.1-C.sub.8 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted pyrrolidinyl, substituted or unsubstituted C.sub.3-C.sub.8 cycloalkyl, disubstituted cyclohexyl, cyclopentyl, substituted or unsubstituted C.sub.5-Cl.sub.2 bicycloalkyl, substituted or unsubstituted adamantyl, --(CH.sub.2).sub.q-group, wherein q is an integer from 1 to 3, under the proviso, if R.sup.6 is selected to be a methylene chain --(CH.sub.2).sub.q-group, R.sup.17 or R.sup.19 are selected to be a methylene chain --(CH.sub.2).sub.s-group, wherein s is an integer from 1 to 3 or a --(CH.sub.2).sub.t-A-group, t is an integer from 1 to 3 and A is selected from O or N, respectively, and R.sup.6 and R.sup.17 or R.sup.6 and R.sup.19 form together a 5 to 8 membered ring system, [0024] or R.sup.6 represents --(CH.sub.2).sub.p-Z, wherein p is an integer from 0 to 6 and Z is selected from the group comprising: [0025] substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, --N(R.sup.7R.sup.8), wherein R.sup.7 and R.sup.8 represent independently from each other --H, or linear or branched substituted or unsubstituted C.sub.1-C.sub.6 alkyl, or Z is selected from --(CR.sup.9R.sup.10R.sup.11), wherein R.sup.9, R.sup.10 and R.sup.11 are independently of each other selected from the group consisting of: [0026] --H, linear or branched substituted or unsubstituted C.sub.1-C.sub.8 alkyl, substituted or unsubstituted aryl or --N(R.sup.12R.sup.13), wherein R.sup.12 and R.sup.13 represent independently of each other --H or linear or branched substituted or unsubstituted C.sub.1-C.sub.6 alkyl, [0027] under the proviso, if Z represents --(CR.sup.9R.sup.10R.sup.11) as defined above, p is selected to be an integer from 0 to 6, and [0028] if Z is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, or --N(R.sup.7R.sup.8) as defined above, p is selected to be an integer from 1 to 6; [0029] L is selected from the group comprising: [0030] wherein R.sup.14 is selected from --H, linear or branched substituted or unsubstituted C.sub.1-C.sub.6 alkyl, --SO.sub.2--R.sup.15, wherein R.sup.15 is selected from linear or branched C.sub.1-C.sub.6 alkyl, or R.sup.14 represents --(CH.sub.2).sub.r--COOR.sup.16, wherein r is an integer from 0 to 6 and R.sup.16 is selected from --H or linear or branched substituted or unsubstituted C.sub.1-C.sub.6 alkyl, [0031] --NR.sup.17--CO--, [0032] wherein R.sup.17 is selected from --H, linear or branched substituted or unsubstituted C.sub.1-C.sub.6 alkyl, or a --(CH.sub.2).sub.s-group, wherein s is an integer from 1 to 3, and [0033] wherein R.sup.6 and R.sup.17 represent both a methylene chain group, R.sup.6 and R.sup.17 may form together a 5 to 8 membered ring system: [0034] wherein R.sup.18 is selected from --H, or linear or branched substituted or unsubstituted C.sub.1-C.sub.6 alkyl, [0035] --CO--NR.sup.19--, [0036] wherein R.sup.19 is selected from --H, linear or branched substituted or unsubstituted C.sub.1-C.sub.6 alkyl, or a --(CH.sub.2).sub.t-A-group, wherein t is an integer from 1 to 3 and A is selected from N or O, and wherein if R.sup.6 represents a --(CH.sub.2).sub.q-group and R.sup.19 represents a --(CH.sub.2).sub.t-A-group, [0037] R.sup.6 and R.sup.19 may form together a 5 to 8 membered ring system [0038] and m is selected to be 0 or 1, [0039] and/or stereoisomeric forms and/or pharmaceutically acceptable salts thereof. [0040] Preferred are compounds having the general formula (I): wherein [0041] each R.sub.1 represents independently R.sub.3, R.sub.5, --H, linear or branched substituted or unsubstituted C.sub.1-C.sub.6 alkyl, linear or branched C.sub.2-C.sub.6 alkenyl or linear or branched C.sub.2-C.sub.6 alkinyl or adamantyl, [0042] R.sub.2 and R.sub.4 are independently selected from the group consisting of: [0043] R.sub.3, R.sub.5, --H, --CN, --NH.sub.2, --NO.sub.2, linear or branched substituted or unsubstituted C.sub.1-C.sub.6 alkyl, linear or branched C.sub.2-C.sub.6 alkenyl or C.sub.2-C.sub.6 linear or branched alkinyl; [0044] R.sub.3 and R'.sub.3 are independently selected from the group consisting of: [0045] a) halogen, represented by --F, --Cl, --Br or --I, [0046] b) C.sub.3-C.sub.8 cycloalkyl, which is optionally substituted by at least one of the groups R.sub.6, R'.sub.6, R.sub.7 or R'.sub.7, [0047] c) C.sub.4-C.sub.12 bicyclo-alkyl, which is optionally substituted by at least one of the groups R.sub.6, R'.sub.6, R.sub.7 or R'.sub.7, [0048] d) aryl , which is optionally substituted by at least one of the groups R.sub.6, R'.sub.6, R.sub.7 or R'.sub.7, [0049] e) X-aryl, which is optionally substituted by at least one of the groups R.sub.6, R'.sub.6, R.sub.7 or R'.sub.7 and wherein X is independently selected from --O--, --NH--, --S--, linear or branched --CH.sub.2--(C.sub.2-C.sub.6 alkyl)-group, linear or branched --CH.sub.2--(C.sub.2-C.sub.6 alkenyl)-group , which is optionally substituted by at least one of the groups R.sub.6, R'.sub.6, R.sub.7 or R'.sub.7, [0050] f) partially or fully saturated 5 or 6 membered heterocyclic ring, which is optionally substituted by at least one of the groups R.sub.6, R'.sub.6, R.sub.7 or R'.sub.7; this heterocyclic ring can be fused to another 5 or 6 membered heterocyclic ring, which is optionally substituted by at least one of the groups R.sub.6, R'.sub.6, R.sub.7 or R'.sub.7, [0051] or a 5 or 6 membered heteroaryl ring, which is optionally substituted by at least one of the groups R.sub.6, R'.sub.6, R.sub.7 or R'.sub.7; this heteroaryl ring can be fused to another partially or fully saturated 5 or 6 membered heterocyclic group, which is optionally substituted by at least one of the groups R.sub.6, R'.sub.6, R.sub.7 or R'.sub.7 or to a 5 or 6 membered heteroaryl ring, which is optionally substituted by at least one of the groups R.sub.6, R'.sub.6, R.sub.7 or R'.sub.7; [0052] g) guanidinyl group, optionally substituted by at least one group R.sub.5 or [0053] h) --Y--(CH.sub.2).sub.p-Z group, wherein Y represents O, S or NR.sub.5 and [0054] Z represents R.sub.5, --OR.sub.5, --N(R.sub.5).sub.2 or --COOR.sub.5, [0055] wherein in the cases, that the group R'.sub.3 represents one of the groups cited under a), g) or h) the indices m and o of the -(L).sub.m-(R.sub.5).sub.o-group are selected to be 0, [0056] R.sub.5 is independently selected from the group consisting of: [0057] --H, R.sub.1, R.sub.2, R.sub.3, R.sub.4, --(CH2).sub.q--COOR.sub.1, --CH.dbd.CH--COOR.sub.1, [0058] --C(R.sub.1).sub.2N(R.sub.1).sub.2, --(CH.sub.2).sub.rN(R.sub.1).sub.2, --NR.sub.1--COOR.sub.1 or --C(R.sub.1).sub.3, [0059] R.sub.6 and R'.sub.6 are independently selected from the group consisting of: [0060] R.sub.1, R.sub.2, R.sub.4, R.sub.5, L-H, --H, --OR.sub.1, --N(R.sub.1).sub.2, --C(R.sub.1).sub.3, --CH(R.sub.1).sub.2, or --CH.sub.2R.sub.1; [0061] R.sub.7 and R'.sub.7 represent independently from each other R.sub.6 and R'.sub.6; [0062] L is selected from the group comprising: [0063] --NR.sub.5--SO.sub.2--, --NR.sub.5--CO--(CH.sub.2).sub.s--, --NH--CO--NH--, --CO--NR.sub.5--, --SO.sub.2--NR.sub.5-- or --NH-- under the proviso, that if m is selected to be 1, o is selected to be 1 as well, [0064] m is independently selected to be 0 or 1, [0065] n is independently selected to be an, integer from 0 to 6, [0066] o is independently selected to be 0 or 1, [0067] p, q, r and s are independently from each other an integer from 0 to 6 [0068] and/or stereoisomeric forms and/or pharmaceutically acceptable salts thereof. [0069] In formula (I) shown above, the group R'.sub.3-L.sub.m-(R.sub.5).sub.o is to be understood in the sense, that the group denoted by R'.sub.3 is optionally substituted by a group -L.sub.m-(R.sub.5).sub.o. This means that if R'.sub.3 is for instance an aryl group, such as phenyl, one of the hydrogen atoms bonded to the aryl group is exchanged by a -L.sub.m-(R.sub.5).sub.o group. [0070] The group aryl as used in items d) and e) of the definition of the groups R.sub.3 and R'.sub.3, preferably describes an aryl group independently selected from the group consisting of phenyl, biphenyl or naphthyl. [0071] In a preferred embodiment of the compounds according to the present invention the rings defined under f) of the definition of the groups R.sup.3 and R'.sup.3 are independently selected to be [0072] wherein [0073] A, B, D, E, F, G, H and I represent independently of each other: [0074] CR.sub.6, C(R.sub.6).sub.2, N, NR.sub.6, O or SR.sub.6 [0075] J and K are independently from each other: C or N, under the proviso that O--O and S--S bonds are excluded and that at least one of the ring atoms in the heterocycle is N, S or O, [0076] and each represent independently from each other a single or a double bond under the proviso that one of the groups R.sub.6 comprised in A, B, D, E, F, G H, I, J and K is exchanged with a -(L).sub.m-(R.sub.5).sub.o-group. [0077] In a further preferred embodiment of the compounds according to the invention R.sub.1, R.sub.2 and R.sub.4 represent independently of each other R.sub.3, R.sub.5, --H, --CH.sub.3, --C.sub.2H.sub.5, --C.sub.3H.sub.7, --CH(CH.sub.3).sub.2, --C.sub.4H.sub.9, --CH.sub.2--CH(CH.sub.3).sub.2, --CH(CH.sub.3)--C.sub.2H.sub.5, --C(CH.sub.3).sub.3, --C.sub.5H.sub.11, --CH.sub.2--C(CH.sub.3).sub.3, --CH(CH.sub.3)--C.sub.3H.sub.7, --CH.sub.2--CH(CH.sub.3)--C.sub.2H.sub.5, --CH(CH.sub.3)--CH(CH.sub.3).sub.2, --C(CH.sub.3).sub.2--C.sub.2H.sub.5, --CH.sub.2--C(CH.sub.3).sub.3, --C.sub.2H.sub.4--CH(CH.sub.3).sub.2, --C.sub.6H.sub.13, --C.sub.3H.sub.6--CH(CH.sub.3).sub.2, --C.sub.2H.sub.4--CH(CH.sub.3)--C.sub.2H.sub.5, --CH(CH.sub.3)--C.sub.4H.sub.9, --CH.sub.2--CH(CH.sub.3)--C.sub.3H.sub.7, --CH(CH.sub.3)--CH.sub.2--CH(CH.sub.3).sub.2, --CH(CH.sub.3)--CH(CH.sub.3)--C.sub.2H.sub.5, --CH.sub.2--CH(CH.sub.3)--CH(CH.sub.3).sub.2, --CH.sub.2--C(CH.sub.3).sub.2--C.sub.2H.sub.5, --C(CH.sub.3).sub.2--C.sub.3H.sub.7, --C(CH.sub.3).sub.2--CH(CH.sub.3).sub.2, --C.sub.2H.sub.4--C(CH.sub.3).sub.3, --CH(CH.sub.3)--C(CH.sub.3).sub.3, --CH.dbd.CH.sub.2, --C.ident.--CH, --CH.sub.2--CH.dbd.CH.sub.2, --C(CH.sub.3).dbd.CH.sub.2, --CH.dbd.CH--CH.sub.3, --C.ident.C--CH.sub.3, --CH.sub.2--C.ident.CH, --C.sub.2H.sub.4--CH.dbd.CH.sub.2, --CH.dbd.CH--C.sub.2H.sub.5, --CH.dbd.C(CH.sub.3).sub.2, --CH.sub.2--CH.dbd.CH--CH.sub.3, --CH.dbd.CH--CH.dbd.CH.sub.2, --C.sub.2H.sub.4.ident.CH, --C.ident.C--C.sub.2H.sub.5, --CH.sub.2--C.ident.C--CH.sub.3, --C.ident.C--CH.dbd.CH.sub.2, --CH.dbd.CH--C.ident.CH, --C.ident.C--C.ident.CH, --C.sub.3H.sub.6--CH.dbd.CH.sub.2, --CH.dbd.CH--C.sub.3H.sub.7, --C.sub.2H.sub.4--CH.dbd.CH--CH.sub.3, --CH.sub.2--CH.dbd.CH--C.sub.2H.sub.5, --CH.sub.2--CH.dbd.CH--CH.dbd.CH.sub.2, --CH.dbd.CH--CH.dbd.CH--CH.sub.3, --CH.dbd.CH--CH.sub.2--CH.dbd.CH.sub.2, --C(CH.sub.3).dbd.CH--CH.dbd.CH.sub.2, --CH.dbd.C(CH.sub.3)CH.dbd.CH.sub.2, --CH.dbd.CH--C(CH.sub.3).dbd.CH.sub.2, --CH.sub.2--CH.dbd.C(CH.sub.3).sub.2, --C(CH.sub.3).dbd.C(CH.sub.3).sub.2, --C.sub.3H.sub.6--C.ident.CH, --C.ident.C--C.sub.3H.sub.7, --C.sub.2H.sub.4--C.ident.C--CH.sub.3, --CH.sub.2--C.ident.C--C.sub.2H.sub.5, --CH.sub.2--C.ident.C--CH.dbd.CH.sub.2, --CH.sub.2--CH.dbd.CH--C.ident.CH, --CH.sub.2--C.ident.C--C.ident.CH, --C.ident.C--CH.dbd.CH--CH.sub.3, --CH.dbd.CH--C.ident.C--CH.sub.3, --C.ident.C--C.ident.C--CH.sub.3, --C.ident.C--CH.sub.2--CH.dbd.CH.sub.2, --CH.dbd.CH--CH.sub.2--C.ident.CH, --C.ident.C--CH.sub.2--C.ident.CH, --C(CH.sub.3).dbd.CH--CH.dbd.CH.sub.2, --CH.dbd.C(CH.sub.3)--CH.dbd.CH.sub.2, --CH.dbd.CH--C(CH.sub.3).dbd.CH.sub.2, --C(CH.sub.3).dbd.CH--C.ident.CH, --CH.dbd.C(CH.sub.3)--C.ident.CH, --C.ident.C--C(CH.sub.3).dbd.CH.sub.2, --C.sub.4H.sub.8--CH.dbd.CH.sub.2. --CH.dbd.CH--C.sub.4H.sub.9, --C.sub.3H.sub.6CH.dbd.CH--CH.sub.3, --CH.sub.2--CH.dbd.CH--C.sub.3H.sub.7, --C.sub.2H.sub.4--CH.dbd.CH--C.sub.2H.sub.5, --CH.sub.2--C(CH.sub.3).dbd.C(CH.sub.3).sub.2, --C.sub.2H.sub.4--CH.dbd.C(CH.sub.3).sub.2, --C.sub.4H.sub.8--C.ident.CH, --C.ident.C--C.sub.4H.sub.9, --C.sub.3H.sub.6--C.ident.C--CH.sub.3, --CH.sub.2--C.ident.C--C.sub.3H.sub.7, --C.sub.2H.sub.4--C.ident.C--C.sub.2H.sub.5; and [0078] R.sub.3 and R'.sub.3 represent independently of each other [0079] and R.sub.5, R.sub.6, R'.sub.6, R.sub.7, R'.sub.7, L, X, Y, Z , n, m, o, p, q, r and s have the meanings as defined before. [0080] In yet a further preferred embodiment of the compounds according to the present invention R.sub.1 represents --H or linear or branched C.sub.1-C.sub.6 alkyl, linear or branched C.sub.2-C.sub.6 alkenyl or linear or C.sub.2-C.sub.6 branched alkinyl, [0081] R.sub.2 and R.sub.4 represent independently of each other --H or linear or branched C.sub.1-C.sub.6 alkyl, linear or branched C.sub.2-C.sub.6 alkenyl, linear or branched [0082] C.sub.2-C.sub.6 alkinyl, --NH.sub.2, --NO.sub.2, --CN, R.sub.3 or R.sub.5; [0083] R.sub.3, R'.sub.3, R.sub.5, R.sub.6, R'.sub.6, R.sub.7, R'.sub.7, L, X, Y, Z , n, m, o, p, q, r and s have the meanings as defined above. [0084] In a further preferred embodiment of the compounds according to the present invention R.sub.1 represents --H or linear or branched C.sub.1-C.sub.6 alkyl, [0085] R.sub.2 and R.sub.4 represent independently of each other --H, --NH.sub.2, linear or branched C.sub.1-C.sub.6 alkyl, [0086] R.sub.3 and R'.sub.3 are independently selected from the group comprising of: [0087] Halogen, X-aryl, which is optionally substituted by at least one of the groups R.sub.6, R'.sub.6, R.sub.7 or R'.sub.7, aryl, which is optionally substituted by at least one of the groups R.sub.6, R'.sub.6, R.sub.7 or R'.sub.7; partially or fully saturated 5 or 6 membered heterocyclic ring, which is optionally substituted by at least one of the groups R.sub.6, R'.sub.6, R.sub.7 or R'.sub.7; this heterocyclic ring can be fused to another 5 or 6 membered heterocyclic ring, which is optionally substituted by at least one of the groups R.sub.6, R'.sub.6, R.sub.7 or R'.sub.7, [0088] 5 or 6 membered heteroaryl ring, which is optionally substituted by at least one of the groups R.sub.6, R'.sub.6, R.sub.7 or R'.sub.7; this heteroaryl ring can be fused to another partially or fully saturated 5 or 6 membered heterocyclic ring, which is optionally substituted by at least one of the groups R.sub.6, R'.sub.6, R.sub.7 or R'.sub.7 or to a 5 or 6 membered heteroaryl ring, which is optionally substituted at least one of the groups R.sub.6, R'.sub.6, R.sub.7 or R'.sub.7, [0089] guanidinyl group, optionally substituted by at least one R.sub.5 group or a --Y--(CH.sub.2).sub.p-Z group, wherein X, Y, Z and p have the meanings as defined in claim 1 and [0090] R.sub.5, R.sub.6, R'.sub.6, R.sub.7, R'.sub.7, L, n, m, o, q, r and s have the meanings as defined above. [0091] In yet another preferred embodiment of the compounds of the present invention R.sub.1 represents --H or linear or branched C.sub.1-C.sub.6 alkyl, [0092] R.sub.2 and R.sub.4 represent independently of each other --H, --NH.sub.2 or linear or branched C.sub.1-C.sub.6 alkyl, [0093] R.sub.3 and R'.sub.3 are independently selected from the group comprising of: [0094] Halogen, X-aryl, which is optionally substituted by at least one of the groups R.sub.6, R'.sub.6, R.sub.7 or R'.sub.7, aryl, which is optionally substituted by at least one of the groups R.sub.6, R'.sub.6, R.sub.7 or R'.sub.7, partially or fully saturated 5 or 6 membered heterocyclic ring, which is optionally substituted by at least one of the groups R.sub.6, R'.sub.6, R.sub.7 or R'.sub.7; this heterocyclic ring can be fused to another 5 or 6 membered heterocyclic ring, which is optionally substituted by at least one of the groups R.sub.6, R'.sub.6, R.sub.7 or R'.sub.7, [0095] 5 or 6 membered heteroaryl ring, which is optionally substituted by at least one of the groups R.sub.6, R'.sub.6, R.sub.7 or R'.sub.7; this heteroaryl ring can be fused to another partially or fully saturated 5 or 6 membered heterocyclic ring, which is optionally substituted by at least one of the groups R.sub.6, R'.sub.6, R.sub.7 or R'.sub.7 or to a 5 or 6 membered heteroaryl ring, which is optionally substituted by at least one of the groups R.sub.6, R'.sub.6, R.sub.7 or R'.sub.7, [0096] guanidinyl group, optionally substituted by at least one R.sub.5 group or a --Y--(CH.sub.2).sub.p-Z group, wherein X, Y, Z and p have the meanings as defined in claim 1; [0097] L represents --NR.sub.5--SO.sub.2--, --NR.sub.5--CO--(CH.sub.2).sub.s--, --NH--CO--NH--, --CO--NR.sub.5-- or --SO.sub.2--NR--, [0098] R.sub.5, R.sub.6, R'.sub.6, R.sub.7, R'.sub.7, n, m, o, q, r and s have the meanings as defined above. [0099] In yet another preferred embodiment of the compounds according to the present invention R.sub.1 represents --H or linear or branched C.sub.1-C.sub.6 alkyl; [0100] R.sub.2 and R.sub.4 represent independently of each other --H or NH.sub.2; [0101] R.sub.3 and R'.sub.3 are independently selected from the group comprising of: [0102] Halogen, X-aryl, which is optionally substituted by at least one of the groups R.sub.6, R'.sub.6, R.sub.7 or R'.sub.7, aryl, which is optionally substituted by at least one of the groups R.sub.6, R'.sub.6, R.sub.7 or R'.sub.7, partially or fully saturated 5 or 6 membered heterocyclic ring which is optionally substituted by at least one of the groups R.sub.6, R'.sub.6, R.sub.7 or R'.sub.7; this ring can be fused to another 5 or 6 membered heterocyclic ring, which is optionally substituted by at least one of the groups R.sub.6, R'.sub.6, R.sub.7 or R'.sub.7, [0103] 5 or 6 membered heteroaryl ring, which is optionally substituted by at least one of the groups R.sub.6, R'.sub.6, R.sub.7 or R'.sub.7; this ring can be fused to another partially or fully saturated 5 or 6 membered heterocyclic ring, which is optionally substituted by at least one of the groups R.sub.6, R'.sub.6, R.sub.7 or R'.sub.7 or to a 5 or 6 membered heteroaryl ring, which is optionally substituted by at least one of the groups R.sub.6, R'.sub.6, R.sub.7 or R'.sub.7, [0104] guanidinyl group, optionally substituted by at least one R.sub.5 group or a --Y--(CH.sub.2).sub.p-Z group, wherein X, Y, Z and p have the meanings as defined in claim 1; [0105] L represents --NR.sub.5--SO.sub.2--, --NR.sub.5--CO--(CH.sub.2).sub.s--, --NH--CO--NH--, --CO--NR.sub.5-- or --SO.sub.2--NR.sub.5--, [0106] R.sub.5 is selected from the group consisting of: [0107] linear or branched C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl , which is optionally substituted by at least one of the groups R.sub.6, R'.sub.6, R.sub.7 or R'.sub.7; C.sub.4-C.sub.12 bicycloalkyl, which is optionally substituted by at least one of the groups R.sub.6, R'.sub.6, R.sub.7 or R'.sub.7, [0108] aryl, which is optionally substituted by at least one of the groups R.sub.6, R'.sub.6, R.sub.7 or R'.sub.7, --CH.sub.2-aryl, which is optionally substituted by at least one of the groups R.sub.6, R'.sub.6, R.sub.7 or R'.sub.7, partially or fully saturated 5 or 6 membered heterocyclic ring, which is optionally substituted by R.sub.6, R'.sub.6, R.sub.7 or R'.sub.7; this ring can be fused to another 5 or 6 membered heterocyclic ring, which is optionally substituted by at least one of the groups R.sub.6, R'.sub.6, R.sub.7 or R'.sub.7, 5 or 6 membered heteroaryl ring, which is optionally substituted by at least one of the groups R.sub.6, R'.sub.6, R.sub.7 or R'.sub.7; this ring can be fused to another partially or fully saturated 5 or 6 membered heterocyclic ring, which is optionally substituted by at least one of the groups R.sub.6, R'.sub.6, R.sub.7 and R'.sub.7 or to a 5 or 6 membered heteroaryl ring, which is optionally substituted by at least one of the groups R.sub.6, R'.sub.6, R.sub.7 or R'.sub.7, --(CH.sub.2).sub.q--COOR.sub.1, wherein R.sub.1 represents --H or a linear or branched C.sub.1-C.sub.6 alkyl, --(CH.sub.2).sub.r--N(R.sub.1).sub.2, wherein R.sub.1 represents independently --H or a linear or branched C.sub.1-C.sub.6 alkyl, --(CR.sub.1).sub.2--N(R.sub.1).sub.2, wherein R.sub.1 represents independently --H or a linear or branched C.sub.1-C.sub.6 alkyl or --C(R.sub.1).sub.3, wherein R1 represents independently --H, a linear or branched C.sub.1-C.sub.6 alkyl or an aryl group, which is optionally substituted by R.sub.6, R'.sub.6, R.sub.7 and R'.sub.7; [0109] R.sub.6, R'.sub.6, R.sub.7, R'.sub.7, n, m, o, p, q, r and s have the meanings as defined above. [0110] In yet another preferred embodiment of the compounds according to the present invention, R1 represents --H or linear or branched C.sub.1-C.sub.6 alkyl, [0111] R.sub.2 and R.sub.4 represent independently of each other --H or NH.sub.2, [0112] R.sub.3 and R'.sub.3 are independently selected from the group comprising of: [0113] Halogen, X-aryl, which is optionally substituted by at least one of the groups R.sub.6, R'.sub.6, R.sub.7 or R'.sub.7, aryl, which is optionally substituted by at least one of the groups R.sub.6, R'.sub.6, R.sub.7 or R'.sub.7, partially or fully saturated 5 or 6 membered heterocyclic ring, which is optionally substituted by at least one of the groups R.sub.6, R'.sub.6, R.sub.7 or R'.sub.7; this heterocyclic ring can be fused to another 5 or 6 membered heterocyclic ring, which is optionally substituted by at least one of the groups R.sub.6, R'.sub.6, R.sub.7 or R'.sub.7, [0114] 5 or 6 membered heteroaryl ring, which is optionally substituted by at least one of the groups R.sub.6, R'.sub.6, R.sub.7 or R'.sub.7; this heteroaryl ring can be fused to another partially or fully saturated 5 or 6 membered heterocyclic ring, which is optionally substituted by at least one of the groups R.sub.6, R'.sub.6, R.sub.7 or R'.sub.7 or to a 5 or 6 membered heteroaryl ring, which is optionally substituted by at least one of the groups R.sub.6, R'.sub.6, R.sub.7 or R'.sub.7or a --Y--(CH.sub.2).sub.p-Z group, wherein X, Y, Z and p have the meanings as defined in claim 1; [0115] L represents --NR.sub.5--SO.sub.2--, --NR.sub.5--CO--(CH.sub.2).sub.n--, --NH--CO--NH--, --CO--NR.sub.5-- or --SO.sub.2--NR.sub.5-- [0116] R.sub.5 is selected from the group comprising: [0117] linear or branched C.sub.1-C.sub.6 alkyl, aryl, which is optionally substituted by at least one of the groups R.sub.6, R'.sub.6, R.sub.7 or R'.sub.7, partially or fully saturated 5 or 6 membered heterocyclic ring, which is optionally substituted by at least one of the groups R.sub.6, R'.sub.6, R.sub.7 or R'.sub.7; this heterocyclic ring can be fused to another 5 or 6 membered heterocyclic ring, which is optionally substituted by R.sub.6, R'.sub.6, R.sub.7 or R'.sub.7, [0118] 5 or 6 membered heteroaryl ring, which is optionally substituted by at least one of the groups R.sub.6, R'.sub.6, R.sub.7 or R'.sub.7; this heteroaryl ring can be fused to another partially or fully saturated 5 or 6 membered heterocyclic ring, which is optionally substituted by at least one of the groups R.sub.6, R'.sub.6, R.sub.7 or R'.sub.7 or to a 5 or 6 membered heteroaryl ring, which is optionally substituted by at least one of the groups R.sub.6, R'.sub.6, R.sub.7 or R'.sub.7, C.sub.3-C.sub.8 cycloalkyl, which is optionally substituted by at least one of the groups R.sub.6, R'.sub.6, R.sub.7 or R'.sub.7 or C.sub.4-C.sub.12 bicycloalkyl, which is optionally substituted by at least one of the groups R.sub.6, R'.sub.6, R.sub.7 or R'.sub.7; [0119] R.sub.6, R'.sub.6, R.sub.7 and R'.sub.7 represent independently of each other: [0120] --H, --F, --Cl, --Br, --I, R.sub.1, --OR.sub.1, --N(R.sub.1).sub.2, --CH.dbd.CH --COOR.sub.1, --(CH.sub.2).sub.qCOOR.sub.1, or a --O--(CH.sub.2).sub.t-aryl, which is optionally substituted by at least one of the groups R.sub.6, R'.sub.6, R.sub.7 or R'.sub.7, wherein in these cases, R.sub.1 is independently selected from --H or linear or branched C.sub.1-C.sub.6 alkyl and t is selected to be an integer from 0 to 6, [0121] n, m, o, p, q, r and s have the meanings as defined above. 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